P1108: EFFICACY OF PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN RELAPSED/REFRACTORY WALDENSTRÖM MACROGLOBULINEMIA: RESULTS FROM THE PHASE 1/2 BRUIN STUDY
Authors: Lydia Scarfò, Manish R. Patel, Toby A. Eyre, Wojciech Jurczak, David Lewis, Thomas Gastinne, Shuo MA, Jonathon B. Cohen, Krish Patel, Jennifer R. Brown, Talha Munir, Ewa Lech-Maranda, Marc S. Hoffmann, Chaitra S. Ujjani, Bita Fakhri, Michael Wang, Koji Izutsu, Hirokazu Nagai, Constantine S. Tam, John F. Seymour, Joanna Rhodes, Julie Vose, Matthew Mckinney, James N. Gerson, Minal A. Barve, Bryone Kuss, Youngil Koh, Wei Gao, Amy S. Ruppert, Richard A. Walgren, Donald E. Tsai, Binoj Nair, Katherine Bao, Anthony R. Mato, Chan Y. Cheah, M Lia Palomba
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have been an important advancement of Waldenström macroglobulinemia (WM) treatment, but they are non-curative, and treatment effectiveness can be limited by intolerance and resistance. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Aims: We report the first sizeable cohort of WM patients from BRUIN. Methods: Patients with previously treated B-cell malignancies, including WM, were eligible for pirtobrutinib monotherapy in dose-escalation/expansion portions of BRUIN. Key endpoints: investigator-assessed ORR and DoR, per modified IWWM6 criteria, and safety. Major response was CR, very good partial response (VGPR)/PR. The response-evaluable cohort was relapsed/refractory (R/R) WM patients in phase 1/2 who had undergone first response assessment/discontinued therapy. The safety cohort was patients with B-cell malignancies receiving at least one pirtobrutinib monotherapy dose (n=725). Data cut: 31 January 2022. Results: Of 78 WM patients(median age: 68 [42-84] years), the median number of prior therapies was 3 (1-11). 66 (85%) patients had received chemotherapy+anti-CD20 antibody (CIT), 61 (78%) ≥1 prior BTKi (≥2: 13/61, 21%), and 50 (64%) CIT+BTKi. Of 61 patients who received ≥1 prior BTKi, 40 (66%) discontinued BTKi due to disease progression. 91% (71/78) received the recommended phase 2 dose (200 mg once daily) as starting dose. The major response rate for 72 response-evaluable patients was 68% (95%CI, 56-79); 17 VGPRs (24%), 32 PRs (44%). At a median response follow-up time of 7.7 months, median DoR among 49 responding patients was not reached (95%CI, 10-NE); 6-month estimated DoR rate: 86% (95%CI, 69-94). Of 55 response-evaluable patients who had received ≥1 prior BTKi, the major response rate was 64% (95%CI, 50-76); 13 VGPRs (24%), 22 PRs (40%) (median DoR also not reached [95%CI, 8-NE], 6-month estimated DoR rate: 83% [95%CI, 60-93]). Of 60 response-evaluable patients who had received CIT, the major response rate was 68% (95%CI, 55-80); 13 VGPRs (22%), 28 PRs (47%). Of 44 response-evaluable patients who had received CIT+BTKi, the major response rate was 64% (95%CI, 48-78); 9 VGPRs (21%), 19 PRs (43%). In the safety cohort of all pirtobrutinib-treated patients with B-cell malignancies (n=725), the most frequent TEAEs were fatigue (26%), diarrhea (22%), contusion (19%); most frequent Grade≥3 TEAE: neutropenia (20%). Low rates of Grade≥3 TEAEs hypertension (3%), hemorrhage (2%), atrial fibrillation/flutter (1%) were observed. Overall, 15 (2%) patients discontinued due to treatment-related AE. Summary/Conclusion: Pirtobrutinib was highly active in WM patients, regardless of prior therapy. Pirtobrutinib was well tolerated with low discontinuation rates. This article was published in Blood (2022) Volume 140 (Supplement 1): 557–560, M Lia Palomba, Manish R Patel, Toby A Eyre, Wojciech Jurczak, David John Lewis, Thomas Gastinne, et al, Efficacy of Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed/ Refractory Waldenström Macroglobulinemia: Results from the Phase 1/2 BRUIN Study, Copyright American Society of Hematology - 64th Annual Meeting (2022). Keywords: Bruton’s tyrosine kinase inhibitor (BTKi), Waldenstrom’s macroglobulinemia, Clinical trial, Non-Hodgkin’s lymphoma